This is a proposal to explore the following hypotheses: (1) The neurochemical/neuroreceptor basis of the pathophysiology of cortisol hypersecretion and dexamethasone resistance in melancholia, is due, at least in part, to limbic muscarinic supersensitivity; (2) Melancholic subjects with abnormal Dexamethasone Suppression Tests (DSTs) will have greater anterior pituitary release of ACTH and Beta-Endorphin in response to central muscarinic pharmacological stimulation than will subjects with normal DSTs, reflecting the above hypothesized limbic muscarinic receptor supersensitivity in melancholia; and (3) Plasma concentrations and ACTH and Beta-Endorphin like cortisol are elevated and resistant to dexamethasone in melancholics with abnormal DSTs and measuring these peptides in the standard 1.0 mg overnight, DST can improve the sensitivity and specificity of the test. A series of psychobiologic strategies are proposed to explore these hypotheses in depressed inpatients, non-depressed psychiatric controls, and normal volunteers on our UCSD Clinical Research Center (sponsored by the NIMH). These studies of muscarinic cholinergic mechanisms in the pathophysiology of depression and cortisol hypersecretion and dexamethasone resistance in melancholia may add to our understanding of the neurochemistry and pathogenesis of depression, as well as increase the sensitivity and clinical utility of the Dexamethasone Suppression Test in the assessment and management of depressed patients.